Regulation of epithelial tissue by hedgehog-like polypeptides, and formulations and uses related thereto

Abstract

The invention provides methods and compositions for modulating hair growth.

I claim:  
     
       1. A method for promoting growth of hair on skin of a mammal, comprising administering an agent to the mammal for a time and under conditions effective to promote growth of hair on the skin of the mammal, wherein the agent is a hedgehog agonist or a patched antagonist that promotes hedgehog signal transduction, and wherein said hedgehog agonist or patched antagonist promotes hedgehog signal transduction by a mechanism selected from 
       (i) binding to patched;  
       (ii) altering the binding or enzymatic activity of a protein involved in hedgehog signal transduction; or  
       (iii) altering expression of a hedgehog protein, a patched protein or a protein involved in hedgehog signal transduction.  
     
     
       2. The method of  claim 1 , wherein the agent is a patched antagonist. 
     
     
       3. The method of  claim 2 , wherein the patched antagonist binds to patched and mimics hedgehog-mediated patched signal transduction. 
     
     
       4. The method of  claim 3 , wherein the binding of the patched antagonist to patched results in upregulation of patched and/or glioma-associated oncogene homolog (gli) expression. 
     
     
       5. The method of  claim 2 , wherein the patched antagonist alters the level of expression of a hedgehog protein, a patched protein or a protein involved in the intracellular signal transduction pathway of patched. 
     
     
       6. The method of  claim 1 , wherein the agent is a hedgehog agonist. 
     
     
       7. The method of  claim 6 , wherein the hedgehog agonist is a peptidomimetic of a hedgehog polypeptide sequence. 
     
     
       8. The method of  claim 6 , wherein the hedgehog agonist is a polypeptide including a hedgehog polypeptide sequence of at least a bioactive extracellular portion of a hedgehog protein. 
     
     
       9. The method of  claim 8 , wherein the polypeptide includes at least 50 contiguous amino acids residues of an N-terminal half of the hedgehog protein. 
     
     
       10. The method of  claim 8 , wherein the polypeptide includes at least 100 contiguous amino acids of an extracellular domain of the hedgehog protein. 
     
     
       11. The method of  claim 8 , wherein the polypeptide includes at least a 19 kd fragment of an extracellular domain of the hedgehog protein. 
     
     
       12. The method of  claim 8 , wherein the hedgehog protein is encoded by a gene of a vertebrate organism. 
     
     
       13. The method of  claim 8 , wherein the polypeptide includes a hedgehog polypeptide sequence represented in SEQ ID No: 21. 
     
     
       14. The method of  claim 13 , wherein the hedgehog polypeptide sequence is an amino acid sequence of a hedgehog protein selected from the group consisting of SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15 and SEQ ID No:16. 
     
     
       15. The method of  claim 8 , wherein the polypeptide includes a hedgehog polypeptide sequence represented in SEQ ID No: 22. 
     
     
       16. The method of  claim 8 , wherein the hedgehog protein is encoded by a human hedgehog gene. 
     
     
       17. The method of  claim 8 , wherein the hedgehog polypeptide sequence is at least 60 percent identical to an amino acid sequence of a hedgehog protein selected from the group consisting of SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15 and SEQ ID No:16. 
     
     
       18. The method of  claim 17 , wherein the hedgehog polypeptide sequence is at least 75 percent identical to an amino acid sequence of a hedgehog protein selected from the group consisting of SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15 and SEQ ID No:16. 
     
     
       19. The method of  claim 17 , wherein the hedgehog polypeptide sequence is at least 85 percent identical to an amino acid sequence of a hedgehog protein selected from the group consisting of SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15 and SEQ ID No:16. 
     
     
       20. The method of  claim 8 , wherein the hedgehog polypeptide sequence is an amino acid sequence of a Sonic hedgehog protein. 
     
     
       21. The method of  claim 8 , wherein the hedgehog polypeptide sequence is an amino acid sequence of a Desert hedgehog protein. 
     
     
       22. The method of  claim 8 , wherein the hedgehog polypeptide sequence is an amino acid sequence of an Indian hedgehog protein. 
     
     
       23. The method of  claim 8 , wherein the hedgehog polypeptide sequence includes amino acid residues 24-193 of SEQ ID No: 15. 
     
     
       24. The method of  claim 8 , wherein the polypeptide is purified to at least 80% by dry weight. 
     
     
       25. The method of  claim 8 , wherein the polypeptide is a recombinantly produced polypeptide. 
     
     
       26. The method of  claim 8 , wherein the polypeptide is a chemically synthesized polypeptide. 
     
     
       27. A method for promoting growth of hair on skin of a mammal, comprising administering a composition to the mammal for a time and under conditions effective to promote growth of hair on the skin of the mammal, wherein said composition comprises an agent and an acceptable carrier or excipient, and wherein the agent is a hedgehog agonist or a patched antagonist that promotes hedgehog signal transduction, and further said hedgehog agonist or patched antagonist promotes hedgehog signal transduction by a mechanism selected from 
       (i) binding to patched;  
       (ii) altering the binding or enzymatic activity of a protein involved in hedgehog signal transduction; or  
       (iii) altering expression of a hedgehog protein, a patched protein or a protein involved in hedgehog signal transduction.  
     
     
       28. The method of  claim 27 , wherein the composition is applied topically.